ATP-responsive hollow nanocapsules for DOX/GOx delivery to enable tumor inhibition with suppressed P-glycoprotein
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Key Laboratory of Silicon Materials, School of Materials Science and Engineering, Zhejiang University, Hangzhou 310027, China Department of Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310000, China 3 ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou 311200, China § Huimin Zhu, Guodong Cao, and Yike Fu contributed equally to this work. 2
© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020 Received: 17 July 2020 / Revised: 17 August 2020 / Accepted: 22 August 2020
ABSTRACT Multidrug resistance (MDR) restricts chemotherapy efficacy due to P-glycoprotein (P-gp) mediated drug efflux, whereas current approaches to suppressing P-gp expression suffer from intrinsic challenges, such as low transfection, high toxicity and poor specificity. Here, hollow ferric-tannic acid complex nanocapsules (HFe-TA), which can be effectively degraded by the reaction with adenosine triphosphate (ATP), are synthesized for the delivery of glucose oxidase (GOx) and doxorubicin (DOX) for tumor treatment. The findings indicate that the intracellular ATP is significantly decreased due to the combined effect of HFe-TA degradation and GOx-mediated glucose consumption. Along with this ATP down-regulation, P-gp expression of tumor cells is suppressed remarkably, which in turn promotes the intracellular accumulation and anticancer efficacy of DOX. In addition, the production of •OH by Fe ions released from HFe-TA is promoted by the by-products of the oxidation of glucose process by GOx. In consequence, HFe-TA nanocapsules loaded with DOX and GOx enable significant inhibition effect to tumors both in vitro and in vivo due to the synergistic effect of cascade reactions. This study has therefore provided an alternative therapeutic platform for effective tumor inhibition with the potential in overcoming intrinsic MDR.
KEYWORDS adenosine triphosphate (ATP)-responsive, P-glycoprotein (P-gp) suppression, nanocapsules, multi-model tumor therapy
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Introduction
Nanotechnology offers tremendous opportunities for tackling cancer disease, especially for the delivery of anticancer drugs to solid tumors. Particles with diverse nanostructures have empowered the drugs with extended plasma circulation time, reduced system toxicity, and promoted dose. In addition, multiple types of drug can be encapsulated and delivered by one nanoparticle for the demand of multi-model synergistic therapy [1–6] and imaging [7, 8]. However, even if anticancer drug is delivered into cancer cells with high dose, the multidrug resistance (MDR) of cancer cells may induce the efflux of drug molecules and thus weaken the therapeutic efficiency. This intrinsic phenomenon has severely hindered the success in the development of chemotherapeutic agents for decades [9, 10]. The most common mechanism of tumor MDR is mediated by adenosine triphosphate (ATP)-binding cassette (ABC) transporters, especially the multidrug resistance protein 1 (MDR1, als
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